Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND) persists in 30-50% of patients. In the ART era, neuropathology has shifted from a rapidly progressing encephalitic condition to a prolonged neurodegenerative disease with pathologic features including astrogliosis, microgliosis, dendritic damage, and especially white matter deficits. White matter alterations include decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. The severity of white matter damage correlates with the amount of time on ART therapy. Transcriptome analysis of HIV patients on ART revealed decreases in genes associated with oligodendrocyte maturation and myelination. These myelin deficits are especially critical in the pediatric population in which myelination is in progress and is necessary to establish critical neural connections that affect motor control, cognition and behavior. Children with vertically transmitted HIV on ART therapy still exhibit memory loss, lack of motor control and executive function and demonstrate white matter deficits and ventricular enlargement by imaging. However, the actual cell and molecular effects on myelin generation caused by products of HIV or the antiretroviral drugs used to treat it have not been studied. The findings in our preliminary studies are consistent with the data from children. Using supernatants from HIV infected macrophages, we show inhibition of the differentiation of oligodendrocytes and myelin protein synthesis in a well-characterized purified tissue culture system. Additionally, we tested select drugs from three classes of antiretrovirals, the protease inhibitor class, the nucleoside reverse transcriptase class, and the integrase inhibitor class and found that select agents inhibit differentiation of oligodendrocyte precursors to mature oligodendrocytes in culture in a dose-dependent manner, independent of cell death. Intravenous administration of ritonavir to mice for only two weeks significantly decreased the expression of several myelin proteins. Further, myelin basic protein (MBP) was significantly decreased in the cortex of adult HIV patients who were on ART and exhibited HAND. We hypothesize that the products of the HIV virus as well as a subset of ART compounds inhibit developmental myelination resulting in motor, behavioral and cognitive deficits. To test this hypothesis, in the first aim we will use the HIV transgenic rat. This animal model of HIV displays deficits in learning and memory and a transcriptome analysis found decreases in key myelin proteins however the actual effects on myelination have not been studied. We will assess developmental myelination by histology, immunochemistry, myelin expression and electron microscopy of myelin structure. In Aim #2, we will determine if the antiretrovirals inhibit or retard developmental myelination in both normal rats and HIV rats during the period of greatest myelin development. Results from these aims should help devise more rational drug therapies without myelin deficits to reduce HAND.